Ozone (O3) is an outdoor air pollutant that causes site-specific damage and remodeling of tissue along the[unreadable] epithelial surface of the lungs. This project is based on the following interrelated hypotheses: the focal[unreadable] nature of O3-induced tissue responses is directly related to the spatial distribution of O3and its reaction[unreadable] products; and the distribution of O3 and its reaction products can be predicted from mathematical transport[unreadable] models that incorporate information about airway anatomy and O3-substrate reactions in the epithelial lining[unreadable] Fluid (ELF). The overarching objective of this work is to develop exposure-dose-response relationships in[unreadable] the respiratory system of 1 month to 12 month old male rhesus monkeys and 1 week to adult Sprague-[unreadable] Dawley rats. In terms of human development, a 6 month old rhesus monkey corresponds to a 1 or 2 year[unreadable] old child. Therefore, the results of this study will lead to a better understanding of the effect that O3 has on[unreadable] human children, and will improve our ability to extrapolate data from developing animal lungs to human[unreadable] ungs. A second objective of this research is to compare the dose-response processes in the nasal cavities[unreadable] to those occurring in the tracheo-bronchial tree. This will allow us to judge whether or not the nose can be[unreadable] used as a sentinel of health effects in the lower respiratory tract.[unreadable] The following specific aims are associated with this project:[unreadable] 1) Develop computer reconstructions of the geometries along axial airway paths in monkey and rat lungs.[unreadable] 2) Formulate models of O3 transport in ELF that incorporate O3 diffusion, substrate efflux and the production[unreadable] of toxic substances by reactions between O3 and substrates.[unreadable] 3) Continue development of axisymmetric single-path models that predict longitudinal dose distributions of[unreadable] O3 and toxic products along axial airway paths in the developing rat and primate lungs.[unreadable] 4) Continue the development of computational fluid dynamics models for simulating the threedimensional[unreadable] dose distributions at selected sites such as the nasal cavities and airway bifurcations.[unreadable] 5) Establish dose-response relationships for rats and for monkeys by correlating the predicted dose[unreadable] distributions with the spatial occurrence of histochemical endpoints.[unreadable] 6) Evaluate the utility of the exposure-dose-response paradigm in extrapolating O3 susceptibility across[unreadable] species, airway sites and exposure patterns in animals at various stages of post-natal development.[unreadable] The simulations of O3 distribution carried out in this project are central to the overall Program Objective to[unreadable] understand the age, site, cell, and post-natal susceptibilities to O3 exposure pattern. This project will have[unreadable] strong interactions with the other components of this Program-Project. Histochemical O3 and biochemical[unreadable] data generated in Projects 1-3 will be crucial for estimating input parameters to the model simulations, for[unreadable] validating models, and for developing dose-response relationships. The Biostatistics and Respiratory[unreadable] Structure Core will provide geometric airway .reconstructions that are essential to the dosimetry simulations.[unreadable] Core C will also assist in the statistical analyses of dose-response relationships and in the evaluation of[unreadable] model precision.[unreadable]